First-in-human phase i study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma

Richard D. Kim, Debashis Sarker, Tim Meyer, Thomas Yau, Teresa Macarulla, Joong Won Park, Su Pin Choo, Antoine Hollebecque, Max W. Sung, Ho Yeong Lim, Vincenzo Mazzaferro, Joerg Trojan, Andrew X. Zhu, Jung Hwan Yoon, Sunil Sharma, Zhong Zhe Lin, Stephen L. Chan, Sandrine Faivre, Lynn G. Feun, Chia Jui YenJean Francois Dufour, Daniel H. Palmer, Josep M. Llovet, Melissa Manoogian, Meera Tugnait, Nicolas Stransky, Margit Hagel, Nancy E. Kohl, Christoph Lengauer, Cori Ann Sherwin, Oleg Schmidt-Kittler, Klaus P. Hoeflich, Hongliang Shi, Beni B. Wolf, Yoon Koo Kang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

163 Citations (Scopus)


Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/ dose-expansion study in advanced HCC using FGF19 expression measured by IHC as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum tolerated dose (600 mg once daily) was expanded in 81 patients. Fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients [median duration of response: 5.3 months (95% CI, 3.7–not reached)] and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC. SIGNIFICANCE: Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection.

Original languageEnglish
Pages (from-to)1696-1707
Number of pages12
JournalCancer discovery
Issue number12
Publication statusPublished - 1 Dec 2019


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